Abstract Summary: Clear cell renal cell carcinoma (ccRCC) is characterized by loss of the von Hippel–Lindau tumor suppressor gene (VHL), and the functional tumorigenic consequences of this loss have been used to develop therapies for advanced ccRCC, such as targeting activation of the HIF pathway. Yao and colleagues elucidate how VHL loss contributes to chromatin alteration at both gene promoters and enhancers/superenhancers, in both an HIF-dependent as well as independent manner, and how this may provide additional targets for therapeutic intervention in advanced ccRCC. Cancer Discov; 7(11); 1221–3. ©2017 AACR. See related article by Yao et al., p. 1284.